Chiral recognition of fenchone and camphor by α-CD through the multi-equilibrium GFN2-xTB quantum approach

Binding constants for host-guest cyclodextrin systems have been estimated recently through the small-cost GFN2-xTB semiempirical quantum method in a multi-equilibrium scope. This work applied such an approach to investigate the inclusion of fenchone and camphor into α-cyclodextrin. The computational cost associated with GFN2-xTB and the supramolecular arrangements automated obtained by UD-APARM allowed the investigation of an unprecedented 18,615 starting systems (8640 for 1:1 guest/CD and 5184 + 2232 + 2559 for 1:2 guest/CD stoichiometry). According to the present study, only 18 (0.21%) for 1:1 associations and 45 (0.45%) for 1:2 associations contribute to the binding constants. The chiral recognition was achieved for the four inclusion compounds investigated: (−)-fenchone@(α-CD)₂, (+)-fenchone@(α-CD)₂, and (−)-camphor@(α-CD)₂ and (+)-camphor@(α-CD)₂. When experimental and theoretical GFN2-xTB (ALPB) binding constants were compared, a linear correlation with an R² equal to 0.9933 was obtained. Estimated error varied from 1 to 3% to adjusted GFN2-xTB values. Furthermore, the theoretical data supported the experimental information that two CD units encapsulate camphor guests, increasing their stabilities. The procedure adopted can be expanded to investigate other 1:1 and 1:2 chiral host-guest systems for which it was addressed that finding out representative host-guest systems correspond to the bottleneck in the use of the discussed GFN2-xTB/UD-APARM multi-equilibrium approach.